Daily Moderate Exercise Is Beneficial and Social Stress Is Detrimental to Disease Pathology in Murine Lupus Nephritis

Abstract

Daily moderate exercise (DME) and stress management are underemphasized in the care of patients with lupus nephritis (LN) due to a poor comprehensive understanding of their potential roles in controlling the inflammatory response. To investigate these effects on murine LN, disease progression was monitored with either DME or social disruption stress (SDR) induction in NZM2410/J mice, which spontaneously develop severe, early-onset LN. SDR of previously established social hierarchies was performed daily for 6 days and DME consisted of treadmill walking (8.5 m/min for 45 min/day). SDR significantly enhanced kidney disease when compared to age-matched, randomly selected control counterparts, as measured by histopathological analysis of H&E staining and immunohistochemistry for complement component 3 (C3) and IgG complex deposition. Conversely, while 88% of non-exercised mice displayed significant renal damage by 43 weeks of age, this was reduced to 45% with exercise. DME also reduced histopathology in kidney tissue and significantly decreased deposits of C3 and IgG complexes. Further examination of renal infiltrates revealed a macrophage-mediated inflammatory response that was significantly induced with SDR and suppressed with DME, which also correlated with expression of inflammatory mediators. Specifically, SDR induced IL-6, TNF-α, IL-1β, and MCP-1, while DME suppressed IL-6, TNF-α, IL-10, CXCL1, and anti-dsDNA autoantibodies. These data demonstrate that psychological stressors and DME have significant, but opposing effects on the chronic inflammation associated with LN; thus identifying and characterizing stress reduction and a daily regimen of physical activity as potential adjunct therapies to complement pharmacological intervention in the management of autoimmune disorders, including LN.

Alpha 1 Antitrypsin Gene Therapy Extends the Lifespan of Lupus-Prone Mice

“…To investigate the effect of hAAT on lupus development, we performed hAAT protein and gene therapy treatment in NZM2410 mice, the parental strain of B6.TC mice that spontaneously develops severe early-onset glomerulonephritis from 20 to 40 weeks of age. 36 Female NZM2410 mice were treated with PBS as a control, clinical-grade AAT (2 mg every 3 days) as protein therapy, or rAAV8-CB-hAAT vector (1 × 10 11 vg) as a gene therapy. The treatment started at 8 weeks of age, before the presence of high levels of autoantibodies and clinical disease.…”

Social Stress Mobilizes Hematopoietic Stem Cells to Establish Persistent Splenic Myelopoiesis

“…Furthermore, our previous studies document a diverse array of exacerbated pathologies associated with the persistent induction of Mo production following social stress. For instance, repeated social defeat stress exacerbated lupus nephritis (Aqel et al, 2017) and allergen-induced airway inflammation (Bailey et al, 2009) and promoted the reactivation of latent herpes simplex virus infections (Padgett et al, 1998). Moreover, social defeat stress increased susceptibility to endotoxic shock (Quan et al, 2001), caused increased lung inflammation (Curry et al, 2010), promoted allodynia and hyperalgesia (Sawicki et al, 2018), impaired learning and memory (McKim et al, 2016a), and prolonged anxiety (McKim et al, 2016b, 2016a).…”

Self-Reported Physical Activity Is Associated with Lupus Nephritis in Systemic Lupus Erythematosus: Data from KORean Lupus Network (KORNET) Registry

“… 33 In contrast, daily moderate exercise attenuated systemic inflammation in response to lipopolysaccharide injection in mice. 34 Recently, Aqel, et al 35 demonstrated that daily moderate exercise improves the inflammatory response of LN in NZM2410/J mice through blocking the expression of inflammatory mediators IL-6, tumor necrosis factor-α, CXCL1, and anti-dsDNA antibodies. Their findings also implicated the possibility of adjunct therapeutic strategy for LN.…”